Towards a quantitative systems level understanding of live-cell mitochondrial physiology in health and disease
Mitochondrial are critically involved in cell cycle regulation, apoptosis, Ca2+ signaling, organismal development, immune responses and dynamic modulation of metabolic capacity. Mitochondrial dysfunction takes a central place in the etiology of many human disorders including diabetes, genetic oxidative phosphorylation defects, cancer and neurodegenerative disorders.
At the (sub)cellular level, metabolism is linked to dynamic alterations in mitochondrial motility, position, structure, mass and function. We focus on gaining a quantitative and mechanistic understanding of the coupling between mitochondrial dynamics and function, and its regulation, at the (sub)cellular level.
To this end, chemical and proteinaceous reporter molecules are introduced in living cells followed by perturbation of mitochondrial dynamics and/or function by genetic and/or chemical means. The effects of these maneuvers are studied using classical biochemical techniques, quantitative (sub)cellular (high-content) live cell microscopy, cellular and mitochondrial single-molecule spectroscopy, image processing and analysis, and quantitative deterministic/stochastic in silico modeling.
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Mitochondrial network in human skin fibroblasts
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This approach is used to obtain a systems level understanding of live-cell mitochondrial physiology by investigating: (I) the pathophysiology of mitochondrial dysfunction in patient cells and knockout mouse models, (II) the physicochemical properties of the mitochondrial matrix, (III) how cells can adapt to mitochondrial dysfunction at the metabolic, structural and functional level, and (IV) which drugs mitigate mitochondrial dysfunction at the cellular and organismal level.